The cerebral cortex is crucial for our highest cognitive and perceptual functions. Its function depends on the precise generation of different neuronal subtypes, and proper wiring of the neurons both within the cerebral cortex and between the cortex and other brain regions. Corticothalamic projection neurons extend axons into the thalamus. They are important in sensory processing, and their dysfunction has been implicated in epilepsy. Subcerebral projection neurons project axons into the midbrain, hindbrain, and spinal cord. These neurons are clinically important since they degenerate in Amyotrophic Lateral Sclerosis (ALS) and other diseases, and are damaged in spinal cord injury. Despite their functional importance and extensive involvement in neurological diseases, the transcription network regulating the generation of distinct cortical projection neuron subtypes remains to be identified. Exciting discoveries have recently been made to illustrate the functions of a network of transcription factors including Fezf2, Tbr1, Sox5 and Satb2, in specifying the identities of distinct projection neuron subtypes. However, our recent and unpublished studies have revealed unexpected complexity in the functions of these genes and their interactions with each other. Thus our understanding of the network of transcription factors regulating cortical neuron fate specification remains incomplete. Lack of such knowledge hinders our effort to understand the biological causes of various neurodevelopmental disorders such as autism, mental retardation, and schizophrenia, and prevents us from designing effective strategies to prevent and treat these diseases. In this grant application, we propose to determine the transcription factor network that specifies the subtype identities and connectivities for subcerebral neurons (Aim 1) and to identify the multiple functions of Satb2 (Aim 2) and Tbr1 (Aim 3) in regulating cortical projection neuron fate specification and differentiation. We will combine mouse genetics, molecular biology and neuroanatomical techniques to achieve these aims.